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Identification of a Fibroblast Growth Factor Receptor 1 Splice Variant That Inhibits Pancreatic Cancer Cell Growth

Departments of ¹ General, Visceral and Transplantation Surgery and ² Clinical Chemistry, University of Ulm, Ulm, Germany and ³ Departments of Medicine, Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire

Requests for reprints: Marko Kornmann, Department of General, Visceral and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany. Phone: 49-731-500-27206; Fax: 49-731-500-27214; E-mail: marko.kornmann{at}medizin.uni-ulm.de.

Fibroblast growth factor receptors (FGFR) play important roles in many biological processes. Nothing is presently known about possible roles of the human FGFR1-IIIb mRNA splice variant. In this study, we characterized for the first time the effects of FGFR1-IIIb expression on the transformed phenotype of human pancreatic cancer cells. The full-length FGFR1-IIIb cDNA was generated and stably expressed in PANC-1 and MIA PaCa-2 pancreatic cancer and TAKA-1 pancreatic ductal cells. FGFR1-IIIb–expressing cells synthesized a glycosylated 110-kDa protein enhancing tyrosine phosphorylation of FGFR substrate-2 on FGF-1 stimulation. The basal anchorage-dependent and anchorage-independent cell growth was significantly inhibited. These effects were associated with a marked reduction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in combination with enhanced activity of p38 MAPK and c-Jun NH₂-terminal kinase. FGFR1-IIIb expression inhibited single-cell movement and in vitro invasion as determined by time-lapse microscopy and Boyden chamber assay as well as in vivo tumor formation and growth in nude mice. Microscopic analysis of the xenograft tumors revealed a reduced Ki-67 labeling and a lower amount of tumor necrosis in FGFR1-IIIb–expressing tumors. Our results show that FGFR1-IIIb is a functional FGFR that inhibits the transformed phenotype of human pancreatic cancer cells. [Cancer Res 2007;67(6):2712–9]

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